Question 1

A 45-year-old woman with depression has been on fluoxetine 20mg for 2 years. She develops treatment-resistant depression and her psychiatrist plans to switch her to phenelzine (an MAOI). Fluoxetine is discontinued. How long must the clinician wait before starting phenelzine?

Accepted Answer

This is the single most commonly tested pharmacokinetic fact about fluoxetine. The standard 14-day SSRI washout (answer A) applies to SSRIs with half-lives of approximately 24-32 hours (sertraline, escitalopram, paroxetine). Fluoxetine requires at least 5 weeks because its active metabolite norfluoxetine has a half-life of 4-16 days, meaning it takes approximately 5 half-lives (roughly 5-6 weeks) for norfluoxetine to clear to negligible levels. Using only the parent drug half-life (answer C) ignores the active metabolite. Answer D is wrong because all SSRIs interact with MAOIs through additive serotonergic mechanisms that can cause serotonin syndrome.

Question 2

A 52-year-old woman with breast cancer is being treated with tamoxifen. She develops major depression. Her oncologist asks you to recommend an antidepressant. Which is the most appropriate choice?

Accepted Answer

This is a high-stakes drug interaction question. Tamoxifen is a prodrug converted by CYP2D6 to endoxifen, its pharmacologically active metabolite. Fluoxetine (answer A) and paroxetine (answer B) are strong CYP2D6 inhibitors that block this conversion, which can reduce endoxifen levels and may compromise tamoxifen's anticancer efficacy. This interaction has influenced oncology guidelines and is a board-testable concept. Bupropion (answer D) is also a moderate CYP2D6 inhibitor and would raise similar concerns, though to a lesser degree. Escitalopram and sertraline are the recommended SSRIs in this context because their CYP2D6 inhibition is minimal to mild.

Question 3

A 14-year-old girl with major depressive disorder and comorbid OCD is not responding to cognitive behavioral therapy alone. Her parents are anxious about medication and ask which antidepressant has the best evidence in her age group. Which of the following is the most accurate response?

Accepted Answer

Fluoxetine has the most extensive pediatric evidence base among SSRIs. It is FDA-approved for depression in children 8+ and OCD in children 7+. The TADS trial provided landmark evidence for fluoxetine plus CBT in adolescent depression. Answer A is too restrictive and contradicts current clinical guidelines. Answer C ignores the substantial differences in pediatric evidence across SSRIs. Answer D is incorrect because escitalopram is approved for adolescent depression (age 12+), not childhood depression, and fluoxetine has broader pediatric data. This patient has both depression and OCD, making fluoxetine particularly appropriate given its FDA approval for both indications in her age group. Close monitoring for suicidality is standard practice, not a reason to withhold treatment.

Fluoxetine

Side Effects Worth Knowing

Sexual Dysfunction

Activation / Anxiety / Insomnia

Nausea

Headache

Weight Effects

Emotional Blunting

Bleeding Risk

Suicidality Risk in Young Adults

Hyponatremia / SIADH

Drug Interactions (CYP2D6)

See This Medication in Action

References & Further Reading